Inhibitors of cyclin-dependent kinases

Abstract

The present invention provides novel compounds of Formulae (I′), (I), (II′), and (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing proliferative diseases (e.g., cancers (e.g., leukemia, acute lymphoblastic leukemia, lymphoma, Burkitt's lymphoma, melanoma, multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma, lung cancer, colorectal cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g., CDK7, CDK12, or CDK13), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.

1 . A compound of Formula (I′): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen, halogen, or optionally substituted alkyl; 
 M is O, S, or NR M ; 
 R M  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; 
 Ring A is optionally substituted monocyclic carbocyclyl, optionally substituted monocyclic heterocyclyl, optionally substituted phenyl, or optionally substituted monocyclic heteroaryl; 
 Ring B cyclohexyl or phenyl attached to L 1  via the ring nitrogen of Ring B; 
 Ring C is optionally substituted monocyclic carbocyclyl, optionally substituted monocyclic heterocyclyl, optionally substituted monocyclic or bicyclic aryl, or optionally substituted monocyclic or bicyclic heteroaryl; 
 each instance of R A , R B , and R C  is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —NO 2 , —N 3 , or optionally substituted acyl; 
 each instance of R a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a  are joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring; 
 each of a1, b1, and c1 is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits; 
 L 1  is —CH 2 —,  lc —S(═O) 2 — lb , —O—, —S—, —NR L1 —, —C(═O)—,  lc —NR L1 C(═O)— lb ,  lc —C(═O)NR L1 — lb ,  lc —OC(═O) lb , or  lc —C(═O)O— lb ; wherein  lb  indicates the point of attachment is to Ring B; and  lc  indicates the point of attachment is to Ring C; 
 L 2  is —O—, —S—, —NR L2 —,  lb —NR L2 C(═O)— lm ,  lb —C(═O)NR L2 — lm ; wherein  lb  indicates the point of attachment is to Ring B; and  lm  indicates the point of attachment is to the heteroaryl ring with M; 
 X is  xm —CH 2 CH 2 — xa ,  xm —CH═CH— xa ,  xm —CH 2 —NR LX xa ,  xm —CH 2 —O—CH 2 — xa ,  xm —CH 2 —NR LX —CH 2 — xa , —O—, —S—, —NR LX —,  xm —O—CH 2 — xa ,  xm —S—CH 2 — xa ,  xm —S—C(═O)CH 2 — xa , or  xm —NR LX —CH 2 — xa ; wherein  xa  indicates the point of attachment is to Ring A; and  xm  indicates the point of attachment is to the heteroaryl ring with M; 
 each of R L1 , R L2 , and R LX  is independently hydrogen, optionally substituted C 1-6  alkyl, or a nitrogen protecting group; 
 R 2  is any of Formulae (i-1)-(i-41): 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein: 
         L 3  is a bond or an optionally substituted C 1-4  hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NR L3a —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NR L3a —, —NR L3a S(═O)—, —S(═O) 2 —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —, wherein R L3a  is hydrogen, optionally substituted C 1-6  alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b  is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b  groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; 
         L 4  is a bond or an optionally substituted, branched or unbranched C 1-6  hydrocarbon chain; 
         each of R E1 , R E2 , and R E3  is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR EE , —CH 2 N(R EE ) 2 , —CH 2 SR EE , —OR EE , —N(R EE ) 2 , —Si(R EE ) 3 , and —SR EE , wherein each occurrence of R EE  is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R EE  groups are joined to form an optionally substituted heterocyclic ring; 
         or R E1  and R E3 , or R E2  and R E3 , or R E1  and R E2  are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; 
         R E4  is a leaving group; 
         R E5  is halogen; 
         R E6  is hydrogen, optionally substituted C 1-6  alkyl, or a nitrogen protecting group; 
         each instance of Y is independently O, S, or NR E7 , wherein R E7  is hydrogen, optionally substituted C 1-6  alkyl, or a nitrogen protecting group; 
         a is 1 or 2; and 
         each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 - 12 . (canceled) 
     
     
         13 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B is cyclohexyl. 
     
     
         14 . The compound of  claim 13 , wherein the compound is of Formulae (I-iv), (I-iv-a), or (I-iv-b): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 - 17 . (canceled) 
     
     
         18 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring C is optionally substituted bicyclic aryl or optionally substituted bicyclic heteroaryl. 
     
     
         19 - 30 . (canceled) 
     
     
         31 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted monocyclic heteroaryl. 
     
     
         32 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted 5-membered heteroaryl or optionally substituted 6-membered heteroaryl. 
     
     
         33 . (canceled) 
     
     
         34 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 each of V 10 , V 11 , V 12 , V 13 , and V 14  is independently be O, S, N, NR A1 , C, or CR A2 , as valency permits; 
 each instance of R A1  is independently selected from the group consisting of hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and a nitrogen protecting group; 
 each instance of R A2  is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —OR A2a , —N(R A2a ) 2 , and —SR A2a ; and 
 each occurrence of R A2a  is independently selected from the group consisting of hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R A2a  groups are joined to form a substituted or unsubstituted heterocyclic ring. 
 
     
     
         35 - 39 . (canceled) 
     
     
         40 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted phenyl. 
     
     
         41 - 48 . (canceled) 
     
     
         49 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted monocyclic heterocyclyl. 
     
     
         50 - 54 . (canceled) 
     
     
         55 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted 6-membered heteroaryl. 
     
     
         56 . (canceled) 
     
     
         57 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1  is —CH 2 —,  lc —S(═O) 2 — lb , —C(═O)—, —NR L1 —, or  lc —NR L1 C(═O)— lb . 
     
     
         58 - 64 . (canceled) 
     
     
         65 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2  is  lb —NR L2 C(═O)— lm ,  lb —C(═O)NR L2 — lm  or —NR L2 —. 
     
     
         66 - 71 . (canceled) 
     
     
         72 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is  xm —S—CH 2 — xa . 
     
     
         73 - 75 . (canceled) 
     
     
         76 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen. 
     
     
         77 - 82 . (canceled) 
     
     
         83 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is of Formula (i-1): 
       
         
           
           
               
               
           
         
       
     
     
         84 - 90 . (canceled) 
     
     
         91 . The compound of  claim 1 , wherein the compound is of one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         92 - 95 . (canceled) 
     
     
         96 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. 
     
     
         97 . (canceled) 
     
     
         98 . A method of treating a proliferative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         99 - 131 . (canceled) 
     
     
         132 . A method of inhibiting the activity of a cyclin-dependent kinase (CDK) or inhibiting transcription in a biological sample or subject, the method comprising administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         133 - 153 . (canceled)